Perturbation of nuclear lamin A causes cell death in chondrocytes

• Published in: Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2012-06, Vol.64 (6), p.1940-1949
• Main Authors: Attur, Mukundan, Ben-Artzi, Ami, Yang, Qing, Al-Mussawir, Hayf E., Worman, Howard J., Palmer, Glyn, Abramson, Steven B.
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Biological and medical sciences; Cartilage, Articular - drug effects; Cartilage, Articular - metabolism; Chondrocytes - drug effects; Chondrocytes - metabolism; Dinoprostone - pharmacology; Diseases of the osteoarticular system; Female; Humans; Interleukin-1beta - pharmacology; Lamin Type A - genetics; Lamin Type A - metabolism; Male; Medical research; Medical sciences; Middle Aged; Osteoarthritis, Knee - genetics; Osteoarthritis, Knee - metabolism; Senescence
• ISSN: 0004-3591; 2326-5191; 1529-0131; 2326-5205
• DOI: 10.1002/art.34360

Objective Mutations in LMNA encoding the A‐type lamins cause several diseases, including those with features of premature aging and skeletal abnormalities. The aim of this study was to examine the expression of lamin A in cartilage from patients with osteoarthritis (OA) and the effects of its overexpression on chondrocyte senescence and apoptosis. Methods Human chondrocyte‐like cells (SW‐1353) were used. RNA isolated from human OA and non‐OA cartilage was used for profiling messenger RNA expression, using Affymetrix microarray analysis. The effects of lamin A overexpression on mitochondrial function and apoptosis were examined by assessing mitochondrial membrane potential, ATP levels, and cytochrome c release, and with a TUNEL assay. Western blotting was performed to determine protein expression. Results Lamin A expression was markedly elevated in OA cartilage samples compared with non‐OA control samples. Western blot analysis confirmed increased expression of lamin A in OA compared with non‐OA cartilage. Interleukin‐1β treatment inhibited lamin A accumulation, whereas treatment with prostaglandin E2 (PGE2) caused a marked increase in lamin A accumulation. These effects of exogenous PGE2 on lamin A expression were mediated via the EP2/EP4 receptors. Transfected chondrocytes that expressed lamin A displayed markers of early senescence/apoptosis. Conclusion The results of this study suggest that lamin A is up‐regulated in OA chondrocytes, and that increased nuclear accumulation of lamin A in response to catabolic stress may account for the premature aging phenotype and apoptosis of OA chondrocytes.